Manipulation of cerebrovascular tone, either directly or indirectly, is an important component of anesthetic and peri-operative care in patients at risk for neurologic injury. This project has the general aim to better characterize the control mechanisms for maintenance of human cerebrovascular tone in health and disease. Such knowledge would greatly facilitate strategies aimed at protecting the brain from permanent damage. In addition to answering mechanistic questions, the proposed studies will also be useful in the development of protocols for acute pharmacologic manipulation of cerebrovascular resistance during anesthesia and surgery in cases where cerebral arterial access is available. This is timely because there is an increasingly frequent use of endovascular surgery for a wide variety of cerebrovascular diseases. It is believed that cerebral blood flow (CBF) is regulated by three main mechanisms: nitric oxide (NO) (predominantly via cGMP), prostaglandins (predominantly via cAMP) and ATP-sensitive K+ channels. This project addresses two specific questions: (1) To what extend does NO influence resting human cerebrovascular tone? (2) What is the relative importance of neuronal versus endothelial nitric oxide synthase (NOS) in influencing resting vascular tone? Our primary hypothesis is that in humans, enothelially-generated NO is a major regulatory influence. Parallel in-vivo (in humans and non-human primates) and in-vitro experiments will be done. In-vivo studies will employ intracarotid infusion of drugs. Intracarotid infusion enables assessment of cerebrovascular effects of a drug in relative isolation from its systemic side-effects. The clinical research will be conducted during cerebral angiography of functionally and angiographically normal cerebral hemispheres. Animal experiments, in baboons, will be conducted in parallel with the clinical research. In vitro studies will be undertaken on intracranial vessels harvested at autopsy from baboons. This parallel model of human and primate is a unique and powerful approach for exploring he full dose-response range of various agonists and antagonists as well as allowing design of optimal protocols utilizing a limited supply of clinical subjects. In addition, in-vitro studies will provide the insight into molecular and cellular mechanisms that regulate cerebrovascular tone. If endothelial-NO is a major determinant of human cerebrovascular tone, neuroprotection using neuronal NOS inhibitors should not compromise tissue perfusion, and intra-arterial NO donors may be useful in manipulation of cerebral perfusion in ischemic brain injury.